JP2018531963A5

JP2018531963A5 -

Info

Publication number: JP2018531963A5
Application number: JP2018521548A
Authority: JP
Filing date: 2016-10-28
Publication date: 2019-12-05
Anticipated expiration: 2036-10-28

Description

多動性障害の１つまたはそれを超える症候を処置、予防または改善するための方法であって、（Ｓ）−（２Ｒ，３Ｒ，１１ｂＲ）−３−イソブチル−９，１０−ジメトキシ−２，３，４，６，７，１１ｂ−ヘキサヒドロ−１Ｈ−ピリド［２，１−ａ］イソキノリン−２−イル２−アミノ−３−メチルブタノエートジ（４−メチルベンゼンスルホネート）（式Ｉ）の結晶性形態またはその同位体変異体；もしくはその溶媒和物を被験体に投与することを含む方法が本明細書で提供される。
本発明は、例えば、以下を提供する：
（項目１）
式Ｉ：

の化合物の結晶形態Ｉ。
（項目２）
約６．３、１７．９および１９．７°の２θ±０．２θにおいて１つまたはそれを超えるピークを含むＸ線粉末回折パターンを有する、項目１に記載の結晶形態。
（項目３）
実質的に図１に示されているＸ線粉末回折パターンを有する、項目１または２に記載の結晶形態。
（項目４）
約２４０℃の開始温度と、約２４３℃におけるピークとを有する吸熱事象を含む示差走査熱量測定サーモグラムを有する、項目１〜３のいずれかに記載の結晶形態。
（項目５）
実質的に図２に示されている示差走査熱量測定サーモグラムを有する、項目１〜４のいずれかに記載の結晶形態。
（項目６）
約２５℃から約１４０℃に加熱した場合に約０．４％未満の質量減少を含む熱重量分析プロットを有する、項目１〜５のいずれかに記載の結晶形態。
（項目７）
実質的に図２に示されている熱重量分析プロットを有する、項目１〜６のいずれかに記載の結晶形態。
（項目８）
約２５℃および約６０％の相対湿度に約３カ月間曝露した際に安定である、項目１〜７のいずれかに記載の結晶形態。
（項目９）
約２５℃および約９２％の相対湿度に曝露した際に安定である、項目１〜８のいずれかに記載の結晶形態。
（項目１０）
約４０℃および約７５％の相対湿度に約３カ月間曝露した際に安定である、項目１〜９のいずれかに記載の結晶形態。
（項目１１）
相対湿度約０％から約９５％への相対湿度増加に供した場合に約１％の質量増加を示す、項目１〜１０のいずれかに記載の結晶形態。
（項目１２）
実質的に図３に示されている重量蒸気系プロットを示す、項目１〜１１のいずれかに記載の結晶形態。
（項目１３）
前記形態が、約９０重量％以上、約９５重量％以上、約９８重量％以上、約９９重量％以上または９９．５重量％以上の結晶形態Ｉを含有する、項目１〜１２のいずれかに記載の結晶形態。
（項目１４）
式Ｉ：

の化合物の結晶形態ＩＩ。
（項目１５）
約５．７、１５．３および２２．５°の２θ±０．２θにおいて１つまたはそれを超えるピークを含むＸ線粉末回折パターンを有する、項目１４に記載の結晶形態。
（項目１６）
実質的に図５に示されているＸ線粉末回折パターンを有する、項目１４または１５のいずれかに記載の結晶形態。
（項目１７）
約１４３℃の開始温度と、約１５５℃におけるピークとを有する吸熱事象および；および約２３２℃の開始温度と、約２３５℃におけるピークとを有する別の吸熱事象を含む示差走査熱量測定サーモグラムを有する、項目１４〜１６のいずれかに記載の結晶形態。
（項目１８）
実質的に図６に示されている示差走査熱量測定サーモグラムを有する、項目１４〜１７のいずれかに記載の結晶形態。
（項目１９）
約２５℃から約１４０℃に加熱した場合に約２．２％の質量減少を含む熱重量分析プロットを有する、項目１４〜１８のいずれかに記載の結晶形態。
（項目２０）
実質的に図６に示されている熱重量分析プロットを有する、項目１４〜１９のいずれかに記載の結晶形態。
（項目２１）
相対湿度約０％から約９５％への相対湿度増加に供した場合に約０．５％の質量増加を示す、項目１４〜２０のいずれかに記載の結晶形態。
（項目２２）
実質的に図７に示されている重量蒸気系プロットを示す、項目１４〜２１のいずれかに記載の結晶形態。
（項目２３）
前記形態が、約９０重量％以上、約９５重量％以上、約９８重量％以上、約９９重量％以上または９９．５重量％以上の結晶形態ＩＩを含有する、項目１４〜２２のいずれかに記載の結晶形態。
（項目２４）
式Ｉ：

の化合物の結晶形態ＩＩＩ。
（項目２５）
約６．３、１８．３、１８．９、１９．８および２０．４°の２θ±０．２θにおいて１つまたはそれを超えるピークを含むＸ線粉末回折パターンを有する、項目２４に記載の結晶形態。
（項目２６）
実質的に図８に示されているＸ線粉末回折パターンを有する、項目２４または２５のいずれかに記載の結晶形態。
（項目２７）
約９３℃、約１５８℃および約２３０℃の温度を有する吸熱事象を含む示差走査熱量測定サーモグラムを有する、項目２４〜２６のいずれかに記載の結晶形態。
（項目２８）
実質的に図９に示されている示差走査熱量測定サーモグラムを有する、項目２４〜２７のいずれかに記載の結晶形態。
（項目２９）
約２５℃から約１４０℃に加熱した場合に約２．７％および約８．８６％の２つの質量減少を含む熱重量分析プロットを有する、項目２４〜２８のいずれかに記載の結晶形態。
（項目３０）
実質的に図９に示されている熱重量分析プロットを有する、項目２４〜２９のいずれかに記載の結晶形態。
（項目３１）
前記形態が、約９０重量％以上、約９５重量％以上、約９８重量％以上、約９９重量％以上または９９．５重量％以上の結晶形態ＩＩＩを含有する、項目２４〜２９のいずれかに記載の結晶形態。
（項目３２）
式Ｉ：

の化合物の結晶形態ＩＶ。
（項目３３）
約６．２、１０．４、１７．９、１９．２、１９．９および２０．２°の２θ±０．２θにおいて１つまたはそれを超えるピークを含むＸ線粉末回折パターンを有する、項目３２に記載の結晶形態。
（項目３４）
実質的に図１０に示されているＸ線粉末回折パターンを有する、項目３２または３３のいずれかに記載の結晶形態。
（項目３５）
約１２８℃、約１５９℃および約２３７℃の温度を有する吸熱事象を含む示差走査熱量測定サーモグラムを有する、項目３２〜３４のいずれかに記載の結晶形態。
（項目３６）
実質的に図１１に示されている示差走査熱量測定サーモグラムを有する、項目３２〜３５のいずれかに記載の結晶形態。
（項目３７）
約２５℃から約１４０℃に加熱した場合に約３．３％の質量減少を含む熱重量分析プロットを有する、項目３２〜３６のいずれかに記載の結晶形態。
（項目３８）
実質的に図１１に示されている熱重量分析プロットを有する、項目３２〜３７のいずれかに記載の結晶形態。
（項目３９）
相対湿度約０％から約９５％への相対湿度増加に供した場合に約３．４％の質量増加を示す、項目３２〜３８のいずれかに記載の結晶形態。
（項目４０）
実質的に図１２に示されている重量蒸気系プロットを示す、項目３２〜３９のいずれかに記載の結晶形態。
（項目４１）
前記形態が、約９０重量％以上、約９５重量％以上、約９８重量％以上、約９９重量％以上または９９．５重量％以上の結晶形態ＩＶを含有する、項目３２〜４０のいずれかに記載の結晶形態。
（項目４２）
式Ｉ：

の化合物の結晶形態Ｖ。
（項目４３）
約６．７、７．９、１０．７、１２．８、１７．１および２３．７°の２θ±０．２θにおいて１つまたはそれを超えるピークを含むＸ線粉末回折パターンを有する、項目４２に記載の結晶形態。
（項目４４）
実質的に図１３に示されているＸ線粉末回折パターンを有する、項目４２または４３のいずれかに記載の結晶形態。
（項目４５）
約１１３℃および約１８１℃の温度を有する吸熱事象を含む示差走査熱量測定サーモグラムを有する、項目４２〜４４のいずれかに記載の結晶形態。
（項目４６）
実質的に図１４に示されている示差走査熱量測定サーモグラムを有する、項目４２〜４５のいずれかに記載の結晶形態。
（項目４７）
約２５℃から約１４０℃に加熱した場合に約４．１％の質量減少を含む熱重量分析プロットを有する、項目４２〜４６のいずれかに記載の結晶形態。
（項目４８）
実質的に図１４に示されている熱重量分析プロットを有する、項目４２〜４７のいずれかに記載の結晶形態。
（項目４９）
相対湿度約０％から約９５％への相対湿度増加に供した場合に約１％の質量増加を示す、項目４２〜４８のいずれかに記載の結晶形態。
（項目５０）
実質的に図１５に示されている重量蒸気系プロットを示す、項目４２〜４９のいずれかに記載の結晶形態。
（項目５１）
前記形態が、約９０重量％以上、約９５重量％以上、約９８重量％以上、約９９重量％以上または９９．５重量％以上の結晶形態Ｖを含有する、項目４２〜５０のいずれかに記載の結晶形態。
（項目５２）
式Ｉ：

の化合物の結晶形態ＶＩ。
（項目５３）
約６．８、８．０、１６．３および１７．５°の２θ±０．２θにおいて１つまたはそれを超えるピークを含むＸ線粉末回折パターンを有する、項目５２に記載の結晶形態。
（項目５４）
実質的に図１６に示されているＸ線粉末回折パターンを有する、項目５２または５３のいずれかに記載の結晶形態。
（項目５５）
約１７５℃および約２３８℃の温度を有する吸熱事象を含む示差走査熱量測定サーモグラムを有する、項目５２〜５４のいずれかに記載の結晶形態。
（項目５６）
実質的に図１７に示されている示差走査熱量測定サーモグラムを有する、項目５２〜５５のいずれかに記載の結晶形態。
（項目５７）
約２５℃から約１４０℃に加熱した場合に約１％の質量減少を含む熱重量分析プロットを有する、項目５２〜５６のいずれかに記載の結晶形態。
（項目５８）
実質的に図１７に示されている熱重量分析プロットを有する、項目５２〜５７のいずれかに記載の結晶形態。
（項目５９）
相対湿度約４０％から約８０％への相対湿度増加に供した場合に約０．５％の質量増加を示す、項目５２〜５８のいずれかに記載の結晶形態。
（項目６０）
相対湿度約０％から約９０％への相対湿度増加に供した場合に約３．１％の質量増加を示す、項目５２〜５９のいずれかに記載の結晶形態。
（項目６１）
実質的に図１８に示されている重量蒸気系プロットを示す、項目５２〜６０のいずれかに記載の結晶形態。
（項目６２）
前記形態が、約９０重量％以上、約９５重量％以上、約９８重量％以上、約９９重量％以上または９９．５重量％以上の結晶形態ＶＩを含有する、項目５２〜６１のいずれかに記載の結晶形態。
（項目６３）
項目１、１４、２４、３２、４２および５２に記載の形態から選択される２つまたはそれを超える結晶形態を含む、混合物。
（項目６４）
非晶質：

。
（項目６５）
式ＩＩ：

の化合物の結晶形態Ｉ。
（項目６６）
約７．２、９．２および１８．０°の２θ±０．２θにおいて１つまたはそれを超えるピークを含むＸ線粉末回折パターンを有する、項目６５に記載の結晶形態。
（項目６７）
実質的に図２０に示されているＸ線粉末回折パターンを有する、項目６５または６６のいずれかに記載の結晶形態。
（項目６８）
約２４０℃の開始温度と、約２５０℃におけるピークとを有する吸熱事象を含む示差走査熱量測定サーモグラムを有する、項目６５〜６７のいずれかに記載の結晶形態。
（項目６９）
実質的に図２１に示されている示差走査熱量測定サーモグラムを有する、項目６５〜６８のいずれかに記載の結晶形態。
（項目７０）
実質的に図２１に示されている熱重量分析プロットを有する、項目６５〜６９のいずれかに記載の結晶形態。
（項目７１）
相対湿度約０％から約９０％への相対湿度増加に供した場合に約１４％の質量増加を示す、項目６５〜７０のいずれかに記載の結晶形態。
（項目７２）
実質的に図２２に示されている重量蒸気系プロットを示す、項目６５〜７１のいずれかに記載の結晶形態。
（項目７３）
前記形態が、約９０重量％以上、約９５重量％以上、約９８重量％以上、約９９重量％以上または９９．５重量％以上の式ＩＩの結晶形態Ｉを含有する、項目６５〜７２のいずれかに記載の結晶形態。
（項目７４）
式ＩＩ：

の化合物の結晶形態ＩＩ。
（項目７５）
約４．８、１３．３および２４．９°の２θ±０．２θにおいて１つまたはそれを超えるピークを含むＸ線粉末回折パターンを有する、項目７４に記載の結晶形態。
（項目７６）
実質的に図２３に示されているＸ線粉末回折パターンを有する、項目７４または７５のいずれかに記載の結晶形態。
（項目７７）
約８０℃の開始温度と、約１０６℃におけるピークとを有する吸熱事象を含む示差走査熱量測定サーモグラムを有する、項目７４〜７６のいずれかに記載の結晶形態。
（項目７８）
実質的に図２４に示されている示差走査熱量測定サーモグラムを有する、項目７４〜７７のいずれかに記載の結晶形態。
（項目７９）
約２５℃から約１４０℃に加熱した場合に約１０％の質量減少を含む熱重量分析プロットを有する、項目７４〜７８のいずれかに記載の結晶形態。
（項目８０）
実質的に図２４に示されている熱重量分析プロットを有する、項目７４〜７９のいずれかに記載の結晶形態。
（項目８１）
相対湿度約７５％から約０％への相対湿度減少に供した場合に約１２％の質量減少を示す、項目７４〜８０のいずれかに記載の結晶形態。
（項目８２）
実質的に図２５に示されている重量蒸気系プロットを示す、項目７４〜８１のいずれかに記載の結晶形態。
（項目８３）
前記形態が、約９０重量％以上、約９５重量％以上、約９８重量％以上、約９９重量％以上または９９．５重量％以上の式ＩＩの結晶形態ＩＩを含有する、項目７４〜８２のいずれかに記載の結晶形態。
（項目８４）
項目６５および７４に記載の形態から選択される２つまたはそれを超える結晶形態を含む、混合物。
（項目８５）
非晶質：

。
（項目８６）
項目１〜６３のいずれかに記載の結晶形態または項目６４もしくは８５に記載の非晶質形態と、薬学的に許容され得る担体とを含む、医薬組成物。
（項目８７）
前記組成物が、経口投与のために製剤化されている、項目８６に記載の医薬組成物。
（項目８８）
前記組成物が、単一剤形として製剤化されている、項目８６または８７に記載の医薬組成物。
（項目８９）
多動性障害の１つまたはそれを超える症候を処置、予防または改善するための方法であって、項目１〜６３のいずれかに記載の結晶形態または項目６４もしくは８５に記載の非晶質形態または項目８６〜８８に記載の医薬組成物を投与することを含む、方法。
（項目９０）
前記多動性障害が、ハンチントン病、遅発性ジスキネジア、トゥレット症候群、ジストニア、ヘミバリズム、舞踏病、老人性舞踏病またはチックである、項目８９に記載の方法。
（項目９１）
前記多動性障害がハンチントン病である、項目９０に記載の方法。
（項目９２）
前記多動性障害が遅発性ジスキネジアである、項目９０に記載の方法。
（項目９３）
前記多動性障害がトゥレット症候群である、項目９０に記載の方法。
（項目９４）
前記多動性障害がチックである、項目９０に記載の方法。
（項目９５）
被験体における小胞モノアミントランスポーターアイソフォーム２を阻害するための方法であって、項目１〜６３のいずれかに記載の結晶形態または項目６４もしくは８５に記載の非晶質形態または項目８６〜８８に記載の医薬組成物を前記被験体に投与することを含む、方法。
（項目９６）
項目１〜６３のいずれかに記載の結晶形態または項目６４もしくは８５に記載の非晶質形態を調製するためのプロセスであって、式Ｉまたは式ＩＩの化合物と溶媒とを接触させることを含む、プロセス。
（項目９７）
前記溶媒が、炭化水素、塩素化炭化水素、アルコール、エーテル、ケトン、エステル、カーボネート、アミド、ニトリル、ニトロ化合物、複素環、水およびそれらの混合物からなる群より選択される、項目９６に記載のプロセス。
（項目９８）
前記溶媒が、アセトニトリル、１，２−ジクロロエタン、ＤＭＦ、１，４−ジオキサン、メタノール、２−メトキシエタノール、ＭＩＢＫ、トルエン、ヘプタン、クメン、アセトン、１−ブタノール、ＭＴＢＥ、エタノール、酢酸エチル、ギ酸エチル、酢酸イソブチル、酢酸イソプロピル、酢酸メチル、ニトロメタン、１−プロパノール、ＩＰＡ、ＭＥＫ、ＴＨＦ、水およびそれらの混合物からなる群より選択される、項目９７に記載のプロセス。
（項目９９）
項目１〜６３のいずれかに記載の結晶形態または項目６４もしくは８５に記載の非晶質形態を調製するためのプロセスであって、（ａ）第１の温度の溶媒中で、式Ｉの化合物のスラリーを調製する工程；および（ｂ）前記スラリーを第２の温度に曝露することによって、前記結晶形態または前記非晶質形態を生成する工程を含む、プロセス。
（項目１００）
前記結晶形態または前記非晶質形態が、前記溶液を前記第２の温度に冷却することによって生成される、項目９９に記載のプロセス。
（項目１０１）
項目１〜６３のいずれかに記載の結晶形態または項目６４もしくは８５に記載の非晶質形態を調製するためのプロセスであって、（ａ）第１の温度の溶媒中で、式Ｉの化合物の溶液を調製する工程；（ｂ）前記溶液を第２の温度に冷却することによって、スラリーを形成する工程；および（ｃ）１回またはそれを超える加熱冷却サイクルで前記スラリーを処理することによって、前記結晶形態または前記非晶質形態を生成する工程を含む、プロセス。
（項目１０２）
前記加熱冷却サイクルが、約−５０〜約１２０℃、約−５０〜約１００℃、約−２０〜約８０℃、約０〜約８０℃、約１０〜約８０℃、約２０〜約８０℃、約２０〜約６０℃または約２０〜約５０℃の温度範囲で実施される、項目１０１に記載のプロセス。
（項目１０３）
前記第１の温度が、約２０〜約２００℃、約２０〜約１５０℃、約２０〜約１００℃または約２０〜約８０℃である、項目９９〜１０２のいずれかに記載のプロセス。
（項目１０４）
前記第２の温度が、約−１００〜１００℃、約−５０〜約５０℃、約−１０〜約３０℃、約２０〜約２００℃、約２０〜約１５０℃または約２０〜約１００℃である、項目９９〜１０３のいずれかに記載のプロセス。
（項目１０５）
前記結晶形態または前記非晶質形態を単離する工程をさらに含む、項目９６〜１０４のいずれかに記載のプロセス。
（項目１０６）
前記溶媒が、炭化水素、塩素化炭化水素、アルコール、エーテル、ケトン、エステル、カーボネート、アミド、ニトリル、ニトロ化合物、複素環、水およびそれらの混合物からなる群より選択される、項目９６〜１０５のいずれかに記載のプロセス。
（項目１０７）
前記溶媒が、アセトニトリル、１，２−ジクロロエタン、ＤＭＦ、１，４−ジオキサン、メタノール、２−メトキシエタノール、ＭＩＢＫ、トルエン、ヘプタン、クメン、アセトン、１−ブタノール、ＭＴＢＥ、エタノール、酢酸エチル、ギ酸エチル、酢酸イソブチル、酢酸イソプロピル、酢酸メチル、ニトロメタン、１−プロパノール、ＩＰＡ、ＭＥＫ、ＴＨＦ、水およびそれらの混合物からなる群より選択される、項目９６〜１０６のいずれかに記載のプロセス。 A method for treating, preventing or ameliorating one or more symptoms of hyperactivity disorder comprising (S)-(2R, 3R, 11bR) -3-isobutyl-9,10-dimethoxy-2, 3,4,6,7,11b-Hexahydro-1H-pyrido [2,1-a] isoquinolin-2-yl 2-amino-3-methylbutanoate di (4-methylbenzenesulfonate) (formula I) Provided herein is a method comprising administering to a subject a crystalline form or an isotopic variant thereof; or a solvate thereof.
The present invention provides, for example:
(Item 1)
Formula I:

Crystal form I of the compound
(Item 2)
The crystalline form of item 1, having an X-ray powder diffraction pattern comprising one or more peaks at 2θ ± 0.2θ of about 6.3, 17.9 and 19.7 °.
(Item 3)
3. A crystalline form according to item 1 or 2, having an X-ray powder diffraction pattern substantially as shown in FIG.
(Item 4)
4. A crystalline form according to any of items 1 to 3, having a differential scanning calorimetry thermogram comprising an endothermic event having an onset temperature of about 240 ° C and a peak at about 243 ° C.
(Item 5)
5. A crystalline form according to any of items 1 to 4, having a differential scanning calorimetry thermogram substantially as shown in FIG.
(Item 6)
6. The crystalline form according to any of items 1-5, having a thermogravimetric analysis plot comprising a mass loss of less than about 0.4% when heated from about 25 ° C to about 140 ° C.
(Item 7)
7. A crystalline form according to any of items 1 to 6, having a thermogravimetric analysis plot substantially as shown in FIG.
(Item 8)
8. The crystalline form according to any of items 1-7, which is stable when exposed to about 25 ° C. and about 60% relative humidity for about 3 months.
(Item 9)
9. The crystalline form of any of items 1-8, which is stable when exposed to about 25 ° C. and about 92% relative humidity.
(Item 10)
10. The crystalline form according to any of items 1-9, which is stable when exposed to about 40 ° C. and about 75% relative humidity for about 3 months.
(Item 11)
11. A crystalline form according to any of items 1 to 10, wherein when subjected to a relative humidity increase from about 0% to about 95% relative humidity, the crystal form exhibits a mass increase of about 1%.
(Item 12)
12. A crystalline form according to any of items 1 to 11, substantially showing a heavy vapor system plot as shown in FIG.
(Item 13)
Any of items 1-12, wherein said form contains about 90% or more, about 95% or more, about 98% or more, about 99% or more, or 99.5% or more of crystalline Form I The crystalline form described.
(Item 14)
Formula I:

Crystal form II of the compound of
(Item 15)
15. A crystalline form according to item 14, having an X-ray powder diffraction pattern comprising one or more peaks at 2θ ± 0.2θ of about 5.7, 15.3 and 22.5 °.
(Item 16)
16. A crystalline form according to any of items 14 or 15, having an X-ray powder diffraction pattern substantially as shown in FIG.
(Item 17)
A differential scanning calorimetry thermogram comprising an endothermic event having an onset temperature of about 143 ° C. and a peak at about 155 ° C .; and another endothermic event having an onset temperature of about 232 ° C. and a peak at about 235 ° C. The crystal form according to any one of Items 14 to 16, comprising:
(Item 18)
18. A crystalline form according to any of items 14-17 having a differential scanning calorimetry thermogram substantially as shown in FIG.
(Item 19)
19. A crystalline form according to any of items 14-18 having a thermogravimetric analysis plot comprising a mass loss of about 2.2% when heated from about 25 ° C to about 140 ° C.
(Item 20)
20. A crystalline form according to any of items 14-19 having a thermogravimetric analysis plot substantially as shown in FIG.
(Item 21)
21. A crystalline form according to any of items 14-20, which exhibits a mass increase of about 0.5% when subjected to a relative humidity increase from about 0% to about 95% relative humidity.
(Item 22)
Item 22. The crystalline form of any of items 14-21, showing a weight vapor system plot substantially as shown in FIG.
(Item 23)
Any of items 14-22, wherein said form contains about 90% or more, about 95% or more, about 98% or more, about 99% or more, or 99.5% or more of crystalline Form II The crystalline form described.
(Item 24)
Formula I:

Crystalline form III of the compound of
(Item 25)
25. Item 24 having an X-ray powder diffraction pattern comprising one or more peaks at 2θ ± 0.2θ of about 6.3, 18.3, 18.9, 19.8 and 20.4 °. Crystal form.
(Item 26)
26. A crystalline form according to any of items 24 or 25, having an X-ray powder diffraction pattern substantially as shown in FIG.
(Item 27)
27. A crystalline form according to any of items 24-26, having a differential scanning calorimetry thermogram comprising an endothermic event having a temperature of about 93 ° C, about 158 ° C and about 230 ° C.
(Item 28)
28. A crystalline form according to any of items 24-27, having a differential scanning calorimetry thermogram substantially as shown in FIG.
(Item 29)
29. A crystalline form according to any of items 24-28, having a thermogravimetric analysis plot comprising two mass reductions of about 2.7% and about 8.86% when heated from about 25C to about 140C.
(Item 30)
30. A crystalline form according to any of items 24-29, having a thermogravimetric analysis plot substantially as shown in FIG.
(Item 31)
Any of paragraphs 24-29, wherein the form contains about 90% or more, about 95% or more, about 98% or more, about 99% or more, or 99.5% or more of crystalline Form III The crystalline form described.
(Item 32)
Formula I:

Crystalline form IV of the compound of
(Item 33)
An item having an X-ray powder diffraction pattern comprising one or more peaks at 2θ ± 0.2θ of about 6.2, 10.4, 17.9, 19.2, 19.9 and 20.2 ° 33. Crystalline form according to 32.
(Item 34)
34. A crystalline form according to any of items 32 or 33, having an X-ray powder diffraction pattern substantially as shown in FIG.
(Item 35)
35. A crystalline form according to any of items 32-34, having a differential scanning calorimetry thermogram comprising an endothermic event having a temperature of about 128 ° C, about 159 ° C and about 237 ° C.
(Item 36)
36. A crystalline form according to any of items 32-35, having a differential scanning calorimetry thermogram substantially as shown in FIG.
(Item 37)
37. The crystalline form according to any of items 32-36, having a thermogravimetric analysis plot comprising a mass loss of about 3.3% when heated from about 25 ° C. to about 140 ° C.
(Item 38)
38. A crystalline form according to any of items 32-37, having a thermogravimetric analysis plot substantially as shown in FIG.
(Item 39)
39. A crystalline form according to any of items 32-38, which exhibits a mass increase of about 3.4% when subjected to a relative humidity increase from about 0% to about 95% relative humidity.
(Item 40)
40. A crystalline form according to any of items 32-39, which shows a weight vapor system plot substantially as shown in FIG.
(Item 41)
Any of paragraphs 32-40, wherein said form contains about 90% or more, about 95% or more, about 98% or more, about 99% or more, or 99.5% or more of crystalline Form IV The crystalline form described.
(Item 42)
Formula I:

Crystal form V of the compound of
(Item 43)
An item having an X-ray powder diffraction pattern comprising one or more peaks at 2θ ± 0.2θ of about 6.7, 7.9, 10.7, 12.8, 17.1 and 23.7 ° 43. Crystalline form according to 42.
(Item 44)
44. A crystalline form according to any of items 42 or 43, having an X-ray powder diffraction pattern substantially as shown in FIG.
(Item 45)
45. A crystalline form according to any of items 42-44, having a differential scanning calorimetry thermogram comprising an endothermic event having a temperature of about 113 ° C and about 181 ° C.
(Item 46)
46. A crystalline form according to any of items 42 to 45, having a differential scanning calorimetry thermogram substantially as shown in FIG.
(Item 47)
47. A crystalline form according to any of items 42-46, having a thermogravimetric analysis plot comprising a mass loss of about 4.1% when heated from about 25 ° C to about 140 ° C.
(Item 48)
48. A crystalline form according to any of items 42 to 47, having a thermogravimetric analysis plot substantially as shown in FIG.
(Item 49)
49. A crystalline form according to any of items 42 to 48, which exhibits a mass increase of about 1% when subjected to a relative humidity increase from about 0% to about 95% relative humidity.
(Item 50)
50. A crystalline form according to any of items 42 to 49, which shows a weight vapor system plot substantially as shown in FIG.
(Item 51)
Any of paragraphs 42-50, wherein the form contains about 90 wt% or more, about 95 wt% or more, about 98 wt% or more, about 99 wt% or more, or 99.5 wt% or more of crystalline Form V The crystalline form described.
(Item 52)
Formula I:

Crystal form VI of the compound of
(Item 53)
53. The crystalline form of item 52, having an X-ray powder diffraction pattern comprising one or more peaks at about 6.8, 8.0, 16.3 and 17.5 ° 2θ ± 0.2θ.
(Item 54)
54. Crystalline form according to any of items 52 or 53, having an X-ray powder diffraction pattern substantially as shown in FIG.
(Item 55)
55. A crystalline form according to any of items 52-54, having a differential scanning calorimetry thermogram comprising an endothermic event having a temperature of about 175 ° C and about 238 ° C.
(Item 56)
56. A crystalline form according to any of items 52-55, having a differential scanning calorimetry thermogram substantially as shown in FIG.
(Item 57)
57. A crystalline form according to any of items 52-56, having a thermogravimetric analysis plot comprising a mass loss of about 1% when heated from about 25C to about 140C.
(Item 58)
58. A crystalline form according to any of items 52-57, having a thermogravimetric analysis plot substantially as shown in FIG.
(Item 59)
59. A crystalline form according to any of items 52-58, which exhibits a mass increase of about 0.5% when subjected to a relative humidity increase from about 40% to about 80% relative humidity.
(Item 60)
60. A crystalline form according to any of items 52-59, which exhibits a mass increase of about 3.1% when subjected to an increase in relative humidity from about 0% to about 90% relative humidity.
(Item 61)
61. A crystalline form according to any of items 52-60, which shows a weight vapor system plot substantially as shown in FIG.
(Item 62)
Any of items 52-61, wherein said form contains about 90% or more, about 95% or more, about 98% or more, about 99% or more, or 99.5% or more of crystalline Form VI The crystalline form described.
(Item 63)
53. A mixture comprising two or more crystalline forms selected from the forms of items 1, 14, 24, 32, 42 and 52.
(Item 64)
Amorphous:

.
(Item 65)
Formula II:

Crystal form I of the compound
(Item 66)
68. A crystalline form according to item 65 having an X-ray powder diffraction pattern comprising one or more peaks at 2θ ± 0.2θ of about 7.2, 9.2 and 18.0 °.
(Item 67)
68. A crystalline form according to any of items 65 or 66, having an X-ray powder diffraction pattern substantially as shown in FIG.
(Item 68)
68. A crystalline form according to any of items 65-67, having a differential scanning calorimetry thermogram comprising an endothermic event having an onset temperature of about 240 ° C. and a peak at about 250 ° C.
(Item 69)
69. Crystal form according to any of items 65-68, having a differential scanning calorimetry thermogram substantially as shown in FIG.
(Item 70)
70. Crystal form according to any of items 65-69, having a thermogravimetric analysis plot substantially as shown in FIG.
(Item 71)
71. A crystalline form according to any of items 65-70, which exhibits a mass increase of about 14% when subjected to a relative humidity increase from about 0% to about 90% relative humidity.
(Item 72)
72. A crystalline form according to any of items 65-71, which shows a weight vapor system plot substantially as shown in FIG.
(Item 73)
Items 65-72, wherein said form contains about 90% or more, about 95% or more, about 98% or more, about 99% or more or 99.5% or more of crystalline Form I of Formula II The crystalline form according to any one.
(Item 74)
Formula II:

Crystal form II of the compound of
(Item 75)
75. A crystalline form according to item 74, having an X-ray powder diffraction pattern comprising one or more peaks at 2θ ± 0.2θ at about 4.8, 13.3 and 24.9 °.
(Item 76)
76. A crystalline form according to any of items 74 or 75, having an X-ray powder diffraction pattern substantially as shown in FIG.
(Item 77)
77. A crystalline form according to any of items 74-76, having a differential scanning calorimetry thermogram comprising an endothermic event having an onset temperature of about 80 ° C. and a peak at about 106 ° C.
(Item 78)
78. Crystal form according to any of items 74-77, having a differential scanning calorimetry thermogram substantially as shown in FIG.
(Item 79)
79. A crystalline form according to any of items 74-78, having a thermogravimetric analysis plot comprising a mass loss of about 10% when heated from about 25 ° C. to about 140 ° C.
(Item 80)
80. A crystalline form according to any of items 74-79, having a thermogravimetric analysis plot substantially as shown in FIG.
(Item 81)
81. A crystalline form according to any of items 74-80, which exhibits a mass loss of about 12% when subjected to a relative humidity reduction from about 75% to about 0% relative humidity.
(Item 82)
82. A crystalline form according to any of items 74 to 81, which shows a weight vapor system plot substantially as shown in FIG.
(Item 83)
Item 74-82, wherein said form contains about 90% or more, about 95% or more, about 98% or more, about 99% or more, or 99.5% or more of crystalline Form II of Formula II The crystalline form according to any one.
(Item 84)
75. A mixture comprising two or more crystalline forms selected from the forms of items 65 and 74.
(Item 85)
Amorphous:

.
(Item 86)
64. A pharmaceutical composition comprising a crystalline form according to any of items 1 to 63 or an amorphous form according to items 64 or 85 and a pharmaceutically acceptable carrier.
(Item 87)
90. The pharmaceutical composition according to item 86, wherein the composition is formulated for oral administration.
(Item 88)
88. A pharmaceutical composition according to item 86 or 87, wherein the composition is formulated as a single dosage form.
(Item 89)
68. A method for treating, preventing or ameliorating one or more symptoms of hyperactivity disorder, the crystal form according to any of items 1 to 63 or the amorphous form according to item 64 or 85 Or a method comprising administering a pharmaceutical composition according to items 86-88.
(Item 90)
90. The method of item 89, wherein the hyperactivity disorder is Huntington's disease, tardive dyskinesia, Tourette syndrome, dystonia, hemivalism, chorea, senile chorea or tic.
(Item 91)
91. A method according to item 90, wherein the hyperactivity disorder is Huntington's disease.
(Item 92)
91. The method of item 90, wherein the hyperactivity disorder is tardive dyskinesia.
(Item 93)
91. The method of item 90, wherein the hyperactivity disorder is Tourette syndrome.
(Item 94)
94. The method of item 90, wherein the hyperactivity disorder is tic.
(Item 95)
68. A method for inhibiting vesicular monoamine transporter isoform 2 in a subject comprising the crystalline form of any of items 1 to 63 or the amorphous form of items 64 or 85 or items 86 to 88. A method comprising administering to the subject a pharmaceutical composition according to.
(Item 96)
68. A process for preparing a crystalline form according to any of items 1 to 63 or an amorphous form according to item 64 or 85, comprising contacting a compound of formula I or formula II with a solvent. ,process.
(Item 97)
99. The item 96, wherein the solvent is selected from the group consisting of hydrocarbons, chlorinated hydrocarbons, alcohols, ethers, ketones, esters, carbonates, amides, nitriles, nitro compounds, heterocyclic rings, water, and mixtures thereof. process.
(Item 98)
The solvent is acetonitrile, 1,2-dichloroethane, DMF, 1,4-dioxane, methanol, 2-methoxyethanol, MIBK, toluene, heptane, cumene, acetone, 1-butanol, MTBE, ethanol, ethyl acetate, ethyl formate. 98. The process of item 97, selected from the group consisting of: isobutyl acetate, isopropyl acetate, methyl acetate, nitromethane, 1-propanol, IPA, MEK, THF, water, and mixtures thereof.
(Item 99)
68. A process for preparing a crystalline form according to any of items 1 to 63 or an amorphous form according to item 64 or 85, comprising: (a) a compound of formula I in a solvent at a first temperature And (b) producing the crystalline form or the amorphous form by exposing the slurry to a second temperature.
(Item 100)
100. The process of item 99, wherein the crystalline form or the amorphous form is produced by cooling the solution to the second temperature.
(Item 101)
68. A process for preparing a crystalline form according to any of items 1 to 63 or an amorphous form according to item 64 or 85, comprising: (a) a compound of formula I in a solvent at a first temperature (B) forming the slurry by cooling the solution to a second temperature; and (c) treating the slurry in one or more heating and cooling cycles. Producing the crystalline form or the amorphous form.
(Item 102)
The heating and cooling cycle is about -50 to about 120 ° C, about -50 to about 100 ° C, about -20 to about 80 ° C, about 0 to about 80 ° C, about 10 to about 80 ° C, about 20 to about 80 ° C. 102. The process of item 101, wherein the process is performed at a temperature range of about 20 to about 60 ° C or about 20 to about 50 ° C.
(Item 103)
103. The process of any of paragraphs 99-102, wherein the first temperature is about 20 to about 200 ° C, about 20 to about 150 ° C, about 20 to about 100 ° C, or about 20 to about 80 ° C.
(Item 104)
The second temperature is about -100 to 100 ° C, about -50 to about 50 ° C, about -10 to about 30 ° C, about 20 to about 200 ° C, about 20 to about 150 ° C, or about 20 to about 100 ° C. 104. The process according to any of items 99 to 103, wherein
(Item 105)
105. The process of any of items 96-104, further comprising isolating the crystalline form or the amorphous form.
(Item 106)
Items 96-105, wherein the solvent is selected from the group consisting of hydrocarbons, chlorinated hydrocarbons, alcohols, ethers, ketones, esters, carbonates, amides, nitriles, nitro compounds, heterocyclic rings, water, and mixtures thereof. The process described in any one.
(Item 107)
The solvent is acetonitrile, 1,2-dichloroethane, DMF, 1,4-dioxane, methanol, 2-methoxyethanol, MIBK, toluene, heptane, cumene, acetone, 1-butanol, MTBE, ethanol, ethyl acetate, ethyl formate. 107. The process according to any of items 96-106, selected from the group consisting of: isobutyl acetate, isopropyl acetate, methyl acetate, nitromethane, 1-propanol, IPA, MEK, THF, water and mixtures thereof.

Claims

Formula I:

Crystal form I of the compound

The crystalline form of claim 1 having an X-ray powder diffraction pattern comprising one or more peaks at 2θ ± 0.2θ of about 6.3, 17.9 and 19.7 °.

3. Crystal form according to claim 1 or 2, having an X-ray powder diffraction pattern substantially as shown in FIG.

4. A crystalline form according to any of claims 1 to 3 having a differential scanning calorimetry thermogram comprising an endothermic event having an onset temperature of about 240 ° C and a peak at about 243 ° C.

5. The crystalline form according to any of claims 1 to 4, having a differential scanning calorimetry thermogram substantially as shown in FIG.

6. The crystalline form of any of claims 1-5 having a thermogravimetric analysis plot comprising a mass loss of less than about 0.4% when heated from about 25C to about 140C.

7. A crystalline form according to any of the preceding claims having a thermogravimetric analysis plot substantially as shown in FIG.

8. The crystalline form according to any of claims 1 to 7, which is stable when exposed to about 25 ° C and about 60% relative humidity for about 3 months.

9. A crystalline form according to any of claims 1 to 8, which is stable when exposed to about 25C and about 92% relative humidity.

10. The crystalline form of any of claims 1-9, which is stable when exposed to about 40 ° C and about 75% relative humidity for about 3 months.

11. A crystalline form according to any of claims 1 to 10, which exhibits a mass increase of about 1% when subjected to a relative humidity increase from about 0% to about 95% relative humidity.

12. Crystal form according to any of the preceding claims, which shows a heavy vapor system plot substantially as shown in FIG.

13. The form of any of claims 1-12, wherein the form contains about 90% or more, about 95% or more, about 98% or more, about 99% or more, or 99.5% or more crystalline Form I. A crystalline form according to 1.

Formula I:

Crystal form II of the compound of

15. The crystalline form of claim 14 having an X-ray powder diffraction pattern comprising one or more peaks at 2θ ± 0.2θ of about 5.7, 15.3 and 22.5 °.

16. A crystalline form according to any of claims 14 or 15, having an X-ray powder diffraction pattern substantially as shown in FIG.

A differential scanning calorimetry thermogram comprising an endothermic event having an onset temperature of about 143 ° C. and a peak at about 155 ° C .; and another endothermic event having an onset temperature of about 232 ° C. and a peak at about 235 ° C. The crystal form according to any one of claims 14 to 16, comprising:

18. A crystalline form according to any of claims 14 to 17 having a differential scanning calorimetry thermogram substantially as shown in FIG.

19. A crystalline form according to any of claims 14-18 having a thermogravimetric analysis plot comprising a mass loss of about 2.2% when heated from about 25C to about 140C.

20. Crystal form according to any of claims 14 to 19, having a thermogravimetric analysis plot substantially as shown in FIG.

21. A crystalline form according to any of claims 14 to 20, which exhibits a mass increase of about 0.5% when subjected to a relative humidity increase from about 0% to about 95% relative humidity.

22. Crystal form according to any of claims 14 to 21, which shows a heavy vapor system plot substantially as shown in FIG.

23. Any of claims 14-22, wherein the form contains about 90% or more, about 95% or more, about 98% or more, about 99% or more, or 99.5% or more of crystalline Form II. A crystalline form according to 1.

Formula I:

Crystalline form III of the compound of

25. An X-ray powder diffraction pattern comprising one or more peaks at 2θ ± 0.2θ at about 6.3, 18.3, 18.9, 19.8 and 20.4 °. Crystal form.

26. A crystalline form according to any of claims 24 or 25 having an X-ray powder diffraction pattern substantially as shown in FIG.

27. A crystalline form according to any of claims 24-26, having a differential scanning calorimetry thermogram comprising endothermic events having temperatures of about 93 ° C, about 158 ° C and about 230 ° C.

28. A crystalline form according to any of claims 24-27 having a differential scanning calorimetry thermogram substantially as shown in FIG.

29. A crystalline form according to any of claims 24-28 having a thermogravimetric analysis plot comprising two mass reductions of about 2.7% and about 8.86% when heated from about 25C to about 140C. .

30. A crystalline form according to any of claims 24-29 having a thermogravimetric analysis plot substantially as shown in FIG.

30. Any of claims 24-29, wherein the form comprises about 90% or more, about 95% or more, about 98% or more, about 99% or more, or 99.5% or more crystalline Form III. A crystalline form according to 1.

Formula I:

Crystalline form IV of the compound of

Having an X-ray powder diffraction pattern comprising one or more peaks at 2θ ± 0.2θ of about 6.2, 10.4, 17.9, 19.2, 19.9 and 20.2 ° Item 33. The crystal form according to Item 32.

34. A crystalline form according to any of claims 32 or 33 having an X-ray powder diffraction pattern substantially as shown in FIG.

35. The crystalline form according to any of claims 32-34, having a differential scanning calorimetry thermogram comprising endothermic events having temperatures of about 128 ° C, about 159 ° C and about 237 ° C.

36. A crystalline form according to any of claims 32-35 having a differential scanning calorimetry thermogram substantially as shown in FIG.

37. The crystalline form of any of claims 32-36, having a thermogravimetric analysis plot comprising a mass loss of about 3.3% when heated from about 25C to about 140C.

38. A crystalline form according to any of claims 32-37, having a thermogravimetric analysis plot substantially as shown in FIG.

39. The crystalline form of any of claims 32-38, wherein the crystalline form exhibits a mass increase of about 3.4% when subjected to a relative humidity increase from about 0% to about 95% relative humidity.

40. A crystalline form according to any of claims 32-39, which shows a weight vapor system plot substantially as shown in FIG.

41. Any of claims 32-40, wherein the form contains about 90 wt% or more, about 95 wt% or more, about 98 wt% or more, about 99 wt% or more, or 99.5 wt% or more of crystalline Form IV. A crystalline form according to 1.

Formula I:

Crystal form V of the compound of

Having an X-ray powder diffraction pattern comprising one or more peaks at 2θ ± 0.2θ of about 6.7, 7.9, 10.7, 12.8, 17.1 and 23.7 ° Item 43. The crystal form according to Item 42.

44. A crystalline form according to any of claims 42 or 43 having an X-ray powder diffraction pattern substantially as shown in FIG.

45. A crystalline form according to any of claims 42 to 44, having a differential scanning calorimetry thermogram comprising an endothermic event having a temperature of about 113 ° C and about 181 ° C.

46. A crystalline form according to any of claims 42 to 45, having a differential scanning calorimetry thermogram substantially as shown in FIG.

47. The crystalline form according to any of claims 42 to 46, having a thermogravimetric analysis plot comprising a mass loss of about 4.1% when heated from about 25C to about 140C.

48. A crystalline form according to any of claims 42 to 47, having a thermogravimetric analysis plot substantially as shown in FIG.

49. A crystalline form according to any of claims 42 to 48, which exhibits a mass increase of about 1% when subjected to a relative humidity increase from about 0% to about 95% relative humidity.

50. A crystalline form according to any of claims 42 to 49, which shows a weight vapor system plot substantially as shown in FIG.

51. Any of claims 42-50, wherein the form contains about 90 wt% or more, about 95 wt% or more, about 98 wt% or more, about 99 wt% or more, or 99.5 wt% or more of crystalline Form V. A crystalline form according to 1.

Formula I:

Crystal form VI of the compound of

53. The crystalline form of claim 52, having an X-ray powder diffraction pattern comprising one or more peaks at 2θ ± 0.2θ of about 6.8, 8.0, 16.3 and 17.5 °.

54. Crystalline form according to any of claims 52 or 53, having an X-ray powder diffraction pattern substantially as shown in FIG.

55. The crystalline form of any of claims 52-54, having a differential scanning calorimetry thermogram comprising an endothermic event having a temperature of about 175 [deg.] C and about 238 [deg.] C.

56. Crystalline form according to any of claims 52 to 55, having a differential scanning calorimetry thermogram substantially as shown in FIG.

57. A crystalline form according to any of claims 52 to 56, having a thermogravimetric analysis plot comprising a mass loss of about 1% when heated from about 25C to about 140C.

58. The crystalline form according to any of claims 52 to 57, having a thermogravimetric analysis plot substantially as shown in FIG.

59. A crystalline form according to any of claims 52 to 58, which exhibits a mass increase of about 0.5% when subjected to a relative humidity increase from about 40% to about 80% relative humidity.

60. The crystalline form of any of claims 52-59, wherein the crystalline form exhibits a mass increase of about 3.1% when subjected to a relative humidity increase from about 0% to about 90% relative humidity.

61. A crystalline form according to any of claims 52-60, which shows a weight vapor system plot substantially as shown in FIG.

62. Any of claims 52-61, wherein the form contains about 90 wt% or more, about 95 wt% or more, about 98 wt% or more, about 99 wt% or more, or 99.5 wt% or more of crystalline Form VI. A crystalline form according to 1.

53. A mixture comprising two or more crystalline forms selected from the forms of claims 1, 14, 24, 32, 42 and 52.

Amorphous:

.

Formula II:

Crystal form I of the compound

66. The crystalline form of claim 65, having an X-ray powder diffraction pattern comprising one or more peaks at 2θ ± 0.2θ of about 7.2, 9.2 and 18.0 °.

67. A crystalline form according to any of claims 65 or 66 having an X-ray powder diffraction pattern substantially as shown in FIG.

68. The crystalline form of any of claims 65-67, having a differential scanning calorimetry thermogram comprising an endothermic event having an onset temperature of about 240 ° C and a peak at about 250 ° C.

69. A crystalline form according to any of claims 65 to 68, having a differential scanning calorimetry thermogram substantially as shown in FIG.

70. The crystalline form of any of claims 65-69, having a thermogravimetric analysis plot substantially as shown in FIG.

71. The crystalline form of any of claims 65-70, wherein the crystalline form exhibits a mass increase of about 14% when subjected to a relative humidity increase from about 0% to about 90% relative humidity.

72. A crystalline form according to any of claims 65 to 71, which shows a heavy vapor system plot substantially as shown in FIG.

75. The form contains about 90 wt% or more, about 95 wt% or more, about 98 wt% or more, about 99 wt% or more, or 99.5 wt% or more of crystalline Form I of Formula II The crystal form according to any one of the above.

Formula II:

Crystal form II of the compound of

75. A crystalline form according to claim 74 having an X-ray powder diffraction pattern comprising one or more peaks at 2θ ± 0.2θ of about 4.8, 13.3 and 24.9 °.

76. A crystalline form according to any of claims 74 or 75, having an X-ray powder diffraction pattern substantially as shown in FIG.

77. A crystalline form according to any of claims 74 to 76 having a differential scanning calorimetry thermogram comprising an endothermic event having an onset temperature of about 80 ° C and a peak at about 106 ° C.

78. A crystalline form according to any of claims 74 to 77 having a differential scanning calorimetry thermogram substantially as shown in FIG.

79. A crystalline form according to any of claims 74 to 78, having a thermogravimetric analysis plot comprising a mass loss of about 10% when heated from about 25C to about 140C.

80. Crystal form according to any of claims 74 to 79, having a thermogravimetric analysis plot substantially as shown in FIG.

81. A crystalline form according to any of claims 74-80, which exhibits a mass loss of about 12% when subjected to a relative humidity reduction from about 75% to about 0% relative humidity.

82. A crystalline form according to any of claims 74 to 81, which shows a weight vapor system plot substantially as shown in FIG.

The form comprises about 90 wt% or more, about 95 wt% or more, about 98 wt% or more, about 99 wt% or more, or 99.5 wt% or more of crystalline Form II of Formula II The crystal form according to any one of the above.

75. A mixture comprising two or more crystalline forms selected from the forms of claims 65 and 74.

Amorphous:

.

64. A pharmaceutical composition comprising the crystalline form of any of claims 1-63 or the amorphous form of claim 64 or 85 and a pharmaceutically acceptable carrier.

90. The pharmaceutical composition of claim 86, wherein the composition is formulated for oral administration.

88. A pharmaceutical composition according to claim 86 or 87, wherein the composition is formulated as a single dosage form.

68. A composition for treating, preventing or ameliorating one or more symptoms of hyperactivity disorder, wherein the composition is a crystalline form according to any of claims 1 to 63 or a non-form according to claim 64 or 85. comprising a pharmaceutical composition according to amorphous form or claims 86 to 88, the composition.

90. The composition of claim 89, wherein the hyperactivity disorder is Huntington's disease, tardive dyskinesia, Tourette syndrome, dystonia, hemivalism, chorea, senile chorea or tic.

92. The composition of claim 90, wherein the hyperactivity disorder is Huntington's disease.

92. The composition of claim 90, wherein the hyperactivity disorder is tardive dyskinesia.

92. The composition of claim 90, wherein the hyperactivity disorder is Tourette syndrome.

92. The composition of claim 90, wherein the hyperactivity disorder is tic.

64. A composition for inhibiting vesicular monoamine transporter isoform 2 in a subject, wherein the composition is a crystalline form according to any of claims 1 to 63 or an amorphous form or claim according to claim 64 or 85. comprising a pharmaceutical composition according to claim 86 to 88, the composition.

A process for preparing a crystalline form according to any of claims 1 to 63 or an amorphous form according to claim 64 or 85, wherein the compound of formula I or formula II is contacted with a solvent. Including the process.

99. The solvent of claim 96, wherein the solvent is selected from the group consisting of hydrocarbons, chlorinated hydrocarbons, alcohols, ethers, ketones, esters, carbonates, amides, nitriles, nitro compounds, heterocyclic rings, water, and mixtures thereof. Process.

The solvent is acetonitrile, 1,2-dichloroethane, DMF, 1,4-dioxane, methanol, 2-methoxyethanol, MIBK, toluene, heptane, cumene, acetone, 1-butanol, MTBE, ethanol, ethyl acetate, ethyl formate. 98. The process of claim 97, selected from the group consisting of: isobutyl acetate, isopropyl acetate, methyl acetate, nitromethane, 1-propanol, IPA, MEK, THF, water, and mixtures thereof.

A process for preparing a crystalline form according to any of claims 1 to 63 or an amorphous form according to claim 64 or 85, wherein: (a) in a solvent at a first temperature, the compound of formula I Preparing a slurry of said compound; and (b) producing said crystalline form or said amorphous form by exposing said slurry to a second temperature.

100. The process of claim 99, wherein the crystalline form or the amorphous form is produced by cooling the solution to the second temperature.

A process for preparing a crystalline form according to any of claims 1 to 63 or an amorphous form according to claim 64 or 85, wherein: (a) in a solvent at a first temperature, the compound of formula I Preparing a solution of the compound of: (b) forming the slurry by cooling the solution to a second temperature; and (c) treating the slurry in one or more heating and cooling cycles. Thereby producing the crystalline form or the amorphous form.

The heating and cooling cycle is about -50 to about 120 ° C, about -50 to about 100 ° C, about -20 to about 80 ° C, about 0 to about 80 ° C, about 10 to about 80 ° C, about 20 to about 80 ° C. 102. The process of claim 101, wherein the process is performed at a temperature range of about 20 to about 60C or about 20 to about 50C.

103. The process of any of claims 99 to 102, wherein the first temperature is about 20 to about 200C, about 20 to about 150C, about 20 to about 100C, or about 20 to about 80C.

The second temperature is about -100 to 100 ° C, about -50 to about 50 ° C, about -10 to about 30 ° C, about 20 to about 200 ° C, about 20 to about 150 ° C, or about 20 to about 100 ° C. 104. The process according to any one of claims 99 to 103, wherein

105. The process of any of claims 96-104, further comprising isolating the crystalline form or the amorphous form.

105. The solvent is selected from the group consisting of hydrocarbons, chlorinated hydrocarbons, alcohols, ethers, ketones, esters, carbonates, amides, nitriles, nitro compounds, heterocyclic rings, water, and mixtures thereof. The process described in any of the above.

The solvent is acetonitrile, 1,2-dichloroethane, DMF, 1,4-dioxane, methanol, 2-methoxyethanol, MIBK, toluene, heptane, cumene, acetone, 1-butanol, MTBE, ethanol, ethyl acetate, ethyl formate. 107. The process according to any of claims 96-106, selected from the group consisting of: isobutyl acetate, isopropyl acetate, methyl acetate, nitromethane, 1-propanol, IPA, MEK, THF, water, and mixtures thereof.